Genetic Variant ANKRD11:p.Thr340Thr (chr16-89285522-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_013275.6(ANKRD11):c.1020G>A(p.Thr340Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0183 in 1,614,004 control chromosomes in the GnomAD database, including 303 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 23 hom., cov: 32)

Exomes 𝑓: 0.019 ( 280 hom. )

Consequence

ANKRD11
NM_013275.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.05

Publications

4 publications found

Variant links:

Genes affected

ANKRD11 (HGNC:21316): (ankyrin repeat domain containing 11) This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]

ANKRD11 Gene-Disease associations (from GenCC):

KBG syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Illumina, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
congenital heart defects, multiple types
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ANKRD11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003126055).

BP6

Variant 16-89285522-C-T is Benign according to our data. Variant chr16-89285522-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2217/152296) while in subpopulation NFE AF = 0.02 (1362/68030). AF 95% confidence interval is 0.0191. There are 23 homozygotes in GnomAd4. There are 1073 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2217 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013275.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD11	NM_013275.6	MANE Select	c.1020G>A	p.Thr340Thr	synonymous	Exon 9 of 13	NP_037407.4
ANKRD11	NM_001256182.2		c.1020G>A	p.Thr340Thr	synonymous	Exon 10 of 14	NP_001243111.1	Q6UB99
ANKRD11	NM_001256183.2		c.1020G>A	p.Thr340Thr	synonymous	Exon 9 of 13	NP_001243112.1	Q6UB99

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANKRD11	ENST00000301030.10	TSL:5 MANE Select	c.1020G>A	p.Thr340Thr	synonymous	Exon 9 of 13	ENSP00000301030.4	Q6UB99
ANKRD11	ENST00000378330.7	TSL:1	c.1020G>A	p.Thr340Thr	synonymous	Exon 10 of 14	ENSP00000367581.2	Q6UB99
ANKRD11	ENST00000642600.2		c.1020G>A	p.Thr340Thr	synonymous	Exon 9 of 13	ENSP00000495226.1	Q6UB99

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2218

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00449

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0201

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00871

Gnomad FIN

AF:

0.0155

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0200

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0166

AC:

4163

AN:

251444

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.0169

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0222

GnomAD4 exome

AF:

0.0187

AC:

27339

AN:

1461708

Hom.:

280

Cov.:

AF XY:

0.0186

AC XY:

13552

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00356

AC:

119

AN:

33444

American (AMR)

AF:

0.0172

AC:

768

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0235

AC:

613

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0114

AC:

985

AN:

86256

European-Finnish (FIN)

AF:

0.0171

AC:

916

AN:

53420

Middle Eastern (MID)

AF:

0.0366

AC:

211

AN:

5768

European-Non Finnish (NFE)

AF:

0.0204

AC:

22692

AN:

1111912

Other (OTH)

AF:

0.0171

AC:

1032

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1751

3502

5254

7005

8756

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

818

1636

2454

3272

4090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2217

AN:

152296

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1073

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00448

AC:

186

AN:

41536

American (AMR)

AF:

0.0200

AC:

306

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00892

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0155

AC:

165

AN:

10616

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0200

AC:

1362

AN:

68030

Other (OTH)

AF:

0.0284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

112

223

335

446

558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0185

Hom.:

Bravo

AF:

0.0150

TwinsUK

AF:

0.0240

AC:

ALSPAC

AF:

0.0234

AC:

ESP6500AA

AF:

0.00660

AC:

ESP6500EA

AF:

0.0230

AC:

198

ExAC

AF:

0.0161

AC:

1956

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0232

EpiControl

AF:

0.0256

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

KBG syndrome (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.2

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.011

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0031

PhyloP100

1.1

Sift4G

Benign

0.65

Vest4

0.21

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over